The p53 gene family occupies central positions in stress response networks throughout the animal kingdom. In humans, p53 is implicated in age-related diseases and altered in most human cancers. As transcription factors, p53 genes mediate selective activation and repression of targets to specify adaptive responses. However, despite extensive characterization, precisely how p53 acts to suppress tumors and mitigate age- related disease remains poorly understood. Since p53 genes are broadly conserved, ancestral properties of these genes offer promising routes towards understanding functions of p53 that become deranged in human diseases. Toward this goal, we are exploring the p53 regulatory network in the Drosophila system. This genetic model offers uniquely powerful opportunities for interrogating conserved networks that support human pathologies and, like its mammalian counterparts, the Drosophila p53 gene specifies adaptive responses to damage that preserve genome stability. Leveraging experimental tools that visualize real-time p53 action in vivo, we discovered that p53 normally contains the activity of transposons, which are mobile elements broadly implicated in sporadic and heritable human disease. We also showed that p53 genetically interacts with the piRNA pathway, an ancient and highly conserved pathway dedicated to the suppression of transposons in all animals. In addition, by exchanging the fly p53 gene with human p53 counterparts, we found that normal human p53 genes can restrain transposons but mutated p53 alleles from cancer patients cannot. These combined discoveries suggest that p53 acts through highly conserved mechanisms to contain transposons. Furthermore, since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates disease by suppressing the movement of transposons. Consistent with this, we uncovered preliminary evidence for unrestrained retrotransposons in p53 mutant mice and in p53-driven human cancers. This initiative inspects the nature, scope and scale of transposon activity provoked by p53 lesions and elucidates mechanisms by which p53 acts to contain mobile elements. Within this framework, we examine whether p53 mutations are permissive for destabilized genomes and disease because they are permissive for deregulated transposons. Our approach integrates genetic models in flies and mice, together with curated human samples. Valuable insights emerging from this initiative may enable novel classifiers that permit us to stratify p53 alleles based on properties that antagonize mobile elements. Since p53 is implicated in age-related diseases and firmly established in the etiology of cancers, these may, in turn, deliver new biomarkers that improve prognosis and inform tailored therapies.